The functional status of the serotonin (5-HT) neurotransmitter system has been studied comparatively in humans and rhesus monkeys using 5-HT-selective agonists and antagonists as pharmacologic probes. Psychophysiologic responses, including blood pressure, neuroendocrine measures, temperature, penile erections, and subjectively assessed as well as objectively rated behavioral changes, are differentially altered by certain agonists, and in certain patient subgroups, as well as by the long-term administration of other psychoactive drugs such as tricyclic antidepressants, lithium, and monoamine oxidase inhibitors. For example, the 5-HT-selective agonist, m-chlorophenylpiperazine (m- CPP), and the 5-HT-releasing agent, fenfluramine, both affect prolactin, cortisol, and food intake, but only m-CPP elicits temperature and behavioral changes. M-CPP but not L-tryptophan was associated with headaches in individuals with a past history or family of migraine. Many other examples support the concept that humans as well as other species have functionally different, independently modulated serotonergic subsystems which appear to correspond, at least in part, to the heterogeneous 5-HT binding sites and neuroanatomical subpathways identified in vivo.